The underlying hypothesis of this Program Project application is that bone marrow stromal cells (MSCs) delivered to brain via an intravenous route can be employed to improve functional outcome after neural injury, specifically, stroke and traumatic brain injury. Three complementary projects and two supporting cores are proposed: Project 1 Treatment of Stroke with MSCs; Project 2/Treatment of Traumatic Brain Injury with MSCs; Project 3/Analysis of MSC Interaction with Tissue. Core A provides the administrative and biostatistical support for the Program Project, and Core B provides the outcome measures of function and behavior after stroke and trauma, measures of cellular and molecular responses to injury and treatment, and the preparation of cells to be employed for treatment. Projects 1 and 2, will determine the optimal means of applying MSC therapy to experimental models in the rat and the mouse of stroke (young and old animals, male, female) and traumatic brain injury (young male), respectively, with safety as an overriding consideration. The hypothesis to be tested is that MSCs in brain evoke the production of trophic factors that alter injured brain to promote functional benefit. Marrow stromal ceils administered to animals intravenously find their way to ischemic or damaged cerebral tissue and foster functional improvement. Thus, under the clinically relevant conditions of intravenous administration, Projects 1 (stroke) and 2 (traumatic brain injury) will optimize and define the boundaries of therapeutic intervention, measure specific neurotrophic factors and structural and morphological changes in treated brain and clarify how the injured brain responds to MSC treatment. Project 3, will employ antibodies, and genetically modified mice and an array of novel technologies to investigate the mechanisms by which treatment of stroke and trauma with MSCs provides functional improvement. A specific set of neurotrophic factors i.e. VEGF, bFGF and BDNF are identified (in Projects I and 2) as key mediators of MSC therapeutic benefit. In Project 3, these factors are manipulated in the MSC treated mouse to determine their roles in MSC therapy of stroke and trauma, with an emphasis on how these factors induced in injured tissue by MSC treatment, promote plasticity and neuroprotection. The long-term goal of this Program Project application is to translate our finding of therapeutic benefit after treatment of experimental stroke and traumatic brain injury with MSCs to the patient.